Open access peer-reviewed chapter

Enzyme-Replacement Therapy in Fabry Disease

Written By

Hanny Sawaf, Angelika L. Erwin, Fang Zhao, Tushar J. Vachharajani and Xiangling Wang

Submitted: 20 November 2021 Reviewed: 18 February 2022 Published: 05 May 2022

DOI: 10.5772/intechopen.103799

From the Edited Volume

Multidisciplinary Experiences in Renal Replacement Therapy

Edited by Ane C.F. Nunes

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Fabry disease is a rare X-linked lysosomal storage disorder due to mutations in the GLA gene causing complete or partial deficiency of the lysosomal enzyme alpha-galactosidase A (a-Gal A). This enzyme deficiency results in tissue accumulation of trihexosylceramide causing the diseases’ systemic manifestations, including acroparesthesia, angiokeratomas, cardiac disease, cerebrovascular manifestations, and kidney disease. Kidney manifestations of Fabry disease can include proteinuria, renal tubular dysfunction, hypertension, and cystic formation. With the relatively recent introduction of enzyme-replacement therapy (ERT), this congenital disorder can now be treated providing these patients with much longer life expectancies and less severe systemic manifestations than before. When started in the appropriate population, ERT is generally continued until a reason for stopping therapy arises. Although ERT is expensive, it has drastically changed the clinical outcome of patients with Fabry disease, and timely initiation of ERT and regular assessments of disease progression by a multidisciplinary care team are critical for the long-term management of these patients.


  • Fabry disease
  • GLA gene
  • alpha-galactosidase A
  • trihexosylceramide
  • enzyme-replacement therapy
  • glycosphingolipids
  • agalsidase
  • kidney disease
  • zebra bodies

1. Introduction

Fabry disease (OMIM # 301500), also called Anderson-Fabry disease, is a rare X-linked lysosomal storage disorder due to mutations in the GLA gene, causing complete or partial deficiency of the lysosomal enzyme alpha-galactosidase A (α-Gal A) [1, 2]. The incidence of Fabry disease is estimated at 1:50,000 to 1:117,000 in males [3]. It has been found among all demographic, ethnic, and racial groups. Fabry disease has been recognized as a heterogeneous, highly complex, and multi-systemic disease associated with a high burden of morbidity and mortality [2].

The α-Gal A enzyme is crucial for glycosphingolipid metabolism. Glycosphingolipids are normal constituents of the plasma membrane as well as the membranes of intracellular organelles. In Fabry disease, the α-Gal A deficiency results in a tissue accumulation of trihexosylceramide causing the disease’s systemic manifestations [1]. Early and often asymptomatic cellular damage typically precedes various degrees of organ affection that can lead to progressive organ failure [2]. Males with less than 1% α-Gal A enzyme activity usually present with classic Fabry disease characterized by onset in childhood or adolescence. Symptoms include acroparesthesia, angiokeratomas, hypohidrosis or anhidrosis, characteristic corneal and lenticular opacities, cardiac disease, cerebrovascular manifestations, proteinuria, and gradual deterioration of renal function, as well as gastrointestinal, auditory, pulmonary, vascular, and psychological manifestations [4, 5, 6, 7, 8, 9, 10, 11, 12]. Males with greater than 1% α-Gal A activity may have later-onset phenotypes and typically develop renal and/or cardiac disease in their fourth to seventh decades of life [13, 14]. Heterozygous females usually have milder symptoms and a later age of onset than males. However, there is broad phenotypic variability and they may have symptoms as severe as those observed in males with the classic form [15, 16], possibly due to skewed X-chromosome inactivation [1, 17].

To date, more than 1000 mutations in the GLA gene have been identified [18], and research on clinically relevant genotype-phenotype relationships is increasingly prioritized [2]. Most of the pathogenic GLA mutations are private, occurring in a single or few families; intra-familial phenotypic variability has been observed, complicating the study of genotype-phenotype correlations [19]. Some mutations can be associated with the classic phenotype that includes nonsense, most of the splicing and frameshift mutations resulting in little or no α-Gal A enzyme activity [19]. In contrast, some missense mutations can encode enzymes with residual α-Gal A activity presenting with the later-onset phenotypes [19, 20, 21].

Current therapeutic approaches for Fabry disease include the reduction of accumulated glycosphingolipids through enzyme-replacement therapy (ERT) and a pharmacological chaperone for a subset of Fabry patients with amenable mutations, along with symptomatic and palliative treatments when needed [22]. In this chapter, we will focus on ERT in Fabry disease, which has clearly demonstrated a modifying effect on serious organ complications and mortality. Kidney manifestations in Fabry disease and the effect of ERT on clinical nephrological outcomes will be highlighted.


2. Kidney manifestations in Fabry disease

Nephropathy caused by intracellular accumulation of globotriaosylceramide (Gb3) in the kidney, is one of the main features of Fabry disease. Kidney manifestations occur in at least 50% of male patients and approximately 20% of female patients [16]. A urinary concentration defect, microalbuminuria, and later overt proteinuria and progressive decline of kidney function are important signs of Fabry nephropathy [23].

2.1 Proteinuria

Proteinuria is the most important biomarker in Fabry nephropathy. Studies showed urinary protein excretion is strongly associated with renal disease progression in men and women with Fabry disease [24]. Proteinuria may be glomerular or tubular in origin and usually appears during the second to third decades of life in affected individuals [23, 25, 26]. Early-onset of proteinuria is not rare and it has been reported in male and female adolescents and in boys as young as 6 years [23]. Approximately 90% of males with Fabry disease developed proteinuria by the age of 50 years [27]. Approximately 30–35% of females with Fabry disease have overt proteinuria with an age of onset that is usually later than in males [27, 28, 29]. Though proteinuria is an early complication of renal injury, it may not be overt in some patients even with advanced kidney disease [28].

The mechanism of proteinuria has not been entirely clear. Gb3 deposits in podocytes have not been directly related to the magnitude of proteinuria [23]. The degree of proteinuria is a major prognostic determinant for more rapidly progressive Fabry nephropathy, particularly in adult male patients, and may also directly contribute to the progression of renal disease [23].

Nephrotic-range proteinuria is uncommon. In a long-term natural history study from the National Institutes of Health (NIH), nephrotic proteinuria was found in 18% of patients with renal disease. The age at onset of nephrotic proteinuria was 40 ± 7 years (range 26–55 yr). The full presentation of nephrotic syndrome was uncommon even in patients who had heavy proteinuria [27].

2.2 Renal tubular dysfunction

Gb3 accumulation in the kidney occurs in all renal cells but preferentially in the glomeruli, distal tubular cells, and vascular smooth muscle cells. Injury of distal tubular cells leads to urinary concentration defects presenting with polyuria, nocturia, and polydipsia, which may be the early signs of Fabry kidney disease [27, 30]. Interestingly, one case report has suggested that screening for mulberry cells (regarded as distal tubular epithelial cells in which Gb3 has accumulated) during urinalysis could be a simple, inexpensive, and noninvasive method for diagnosing Fabry nephropathy in the absence of proteinuria [31, 32]. Gb3 deposition in proximal tubules may rarely lead to proximal renal tubular acidosis or even Fanconi syndrome. The urine sediment in Fabry disease may contain oval fat bodies, which are renal tubular epithelial cells or cell fragments with lipid inclusions. Under microscopy using crossed polarization filters, these oval fat bodies demonstrate a typical Maltese cross configuration with a lamellar appearance [27].

2.3 Chronic kidney disease

Initially, patients with Fabry disease may have glomerular hyperfiltration at a rate similar to diabetic nephropathy [23, 33]. However, when the number of damaged nephrons reaches a critical level that cannot maintain adequate glomerular filtration, there will be a rapid decline in GFR [23]. CKD is prevalent in untreated patients with Fabry disease and typically progresses to end-stage renal disease (ESRD). In a cross-sectional retrospective analysis of the natural history of glomerular filtration rate (estimated-eGFR), albuminuria, and proteinuria in 1262 adult patients (585 males, 677 females) using data from the Fabry Registry before treatment with ERT, chronic kidney disease (CKD) stages 1 or 2 were found in 72% of males and 87% of females. CKD with eGFR <60 ml/min/1.73 m [2] was found in 28% of males and 13% of females, while in patients aged >40 years, the percentage increased to 45 and 20% [28]. Without ERT, progression rates of renal insufficiency can be as high as seen in diabetic nephropathy [23]. In the NIH series described above, 39 of 105 patients developed CKD defined as a serum creatinine concentration ≥ 1.5 mg/dL, and the median age of CKD onset and ESRD was 42 years and 47 years, respectively, with a time of progression from onset of CKD to ESRD 4 ± 3 years (range 1–13 yr) [27].

2.4 Hypertension

Hypertension is not a common early finding in patients with Fabry disease but becomes more prevalent with disease progression [23]. In the NIH series, hypertension was present in 31 patients (30%) with onset at age 38 ± 11 years (range 14–54 yr). Thirty-five percent of patients developed hypertension before the onset of CKD, 12% of patients had a simultaneous diagnosis of hypertension and CKD, and 53% of patients developed hypertension 5 ± 5 years after the onset of CKD [27], suggesting that the onset of CKD was followed by the development of hypertension in most patients.

2.5 Renal sinus and parapelvic cysts

Renal cysts are common, particularly in older men. Studies from potential living kidney donors showed that a cortical, medullary, or parapelvic cyst ≥5 mm was present in 12%, 14%, and 2.8%, respectively [34]. Renal sinus and parapelvic cysts are more prevalent in patients with Fabry disease compared to the general population and are considered as a distinguishing feature in Fabry disease [35]. In a cross-sectional case-control study with 24 patients affected with classic Fabry disease (mean age 36.1 ± 8.1 years, median 37 years, range 20–48 years), prospective renal imaging evaluation with magnetic resonance imaging (MRI) and computed tomography (CT) showed 50% of Fabry disease patients had renal sinus cysts, compared to one individual (7%) in the control group [35]. The etiology and mechanism of sinus cyst formation in Fabry disease remain unclear.

2.6 Renal pathology

Renal biopsy is important not only for confirming the diagnosis, but also to show renal damage that can occur in some patients with minimal or no evidence of renal disease on standard tests [23]. By light microscopy, the cells, especially podocytes, parietal epithelial cells, and distal tubular epithelial cells, appear vacuolated because the accumulated glycosphingolipid inclusions are removed during tissue processing for paraffin embedding. Hyaline-like material accumulates in the media of arteries and arterioles and sometimes in the mesangial regions [36]. Immunofluorescence is typically negative. By electron microscopy, podocytes are filled with osmiophilic, granular-to-lamellated membrane structures (zebra bodies) [23, 27, 36].


3. Enzyme-replacement therapy (ERT)

Before ERT was available, a reduced life span of about 25 years in males and 10 years in females was expected compared with the general population [2, 37]. Clinical research with follow-up data clearly demonstrates a modifying effect of ERT on serious organ complications and mortality. ERT has been available for the treatment of Fabry disease since 2001 in Europe and since 2003 in the USA. Licensed ERT treatments include agalsidase alfa (Replagal™, Shire Human Genetic Therapies/Takeda Pharmaceuticals Europe Ltd., London, UK), agalsidase beta (Fabrazyme™, Sanofi Genzyme, Cambridge, MA), and agalsidase beta biosimilar (Fabagal™, Isu-Abxis, South Korea). Agalsidase beta is licensed in both the USA and Europe, while agalsidase alfa is not licensed in the USA. Fabagal is approved in South Korea [22]. Agalsidase alfa is produced in a genetically engineered human cell line and agalsidase beta is produced in a Chinese hamster ovary cell line [38].


4. Efficacy of ERT

In a 20-week multicenter, randomized, placebo-controlled, double-blind phase 3 clinical trial of 58 patients who were at least 16 years old and had enzymatically confirmed classic Fabry disease, agalsidase beta at 1 mg/kg/2 weeks cleared microvascular endothelial deposits of Gb3 from the kidneys, heart, and skin, reversing the chief clinical manifestation of this disease [39].

Further investigation was performed to analyze the pre- and post-treatment renal biopsies from these Fabry disease patients and the authors found that after 11 months of ERT, complete clearance of glycolipid storage was noted from the endothelium of all vasculature, the mesangial cells of the glomerulus, and interstitial cells of the cortex, while moderate clearance was noted from the smooth muscle cells of arterioles and small arteries [40]. Limited clearance of glycolipid storage was also observed from podocytes and distal tubular epithelium [40].

An open-label, phase 3 extension study was conducted involving these 58 patients who completed the 20-week study and were transitioned to an extension trial to receive agalsidase beta biweekly at 1 mg/kg for up to an additional 54 months [41]. Authors reported by month 54 all assessable patients maintained clearance of glycolipid storage clearance from multiple renal cell types, including renal capillary endothelial cells, mesangial cells, and noncapillary endothelial cells. Sustained clearance of skin and heart capillary endothelium was also demonstrated by month 54. Mean plasma Gb3 levels remained controlled in the normal range and kidney function remained stable in patients with data available. This study suggested baseline proteinuria (>1 g/24 h), >50% glomerulosclerosis, and age > 40 years at treatment baseline as important factors that limited renal response to therapy [41].

Furthermore, a study was conducted to investigate the long-term outcomes in 52 of these 58 patients including severe clinical events, renal function, and cardiac structure following treatment with agalsidase beta (1 mg/kg/2 weeks) over a 10-year median follow-up period. Authors reported that 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period [17]. Mean slopes for eGFR for low renal involvement and high renal involvement were −1.89 mL/min/1.73 m2/year and −6.82 mL/min/1.73 m2/year, respectively [17]. Patients with low renal involvement started therapy 13 years younger than those with high renal involvement. This 10-year study documented the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease and suggested patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy [17].

In addition, a recent meta-analysis with the evidence base including four Sanofi Genzyme studies and six studies from a systematic literature review suggested that treated (agalsidase beta) patients experienced a slower median eGFR decrease [2.46 mL/min/1.73 m2/year slower; 95% confidence interval (CI) 0.63–4.29; P ¼ 0.0087] than comparable untreated patients [22].


5. Initiation of ERT

Initiation of ERT requires a fully confirmed diagnosis of Fabry disease [19]. The patient/patient’s family should be included in the decision-making process and should have a good understanding of the impact of the treatment as well as potential adverse reactions. The initiation of lifelong ERT infusion therapy is a major decision with important implications for both the patient, particularly the pediatric patient, and the family [42]. Treatment and follow-up assessments should ideally be led by a physician who is experienced in the management of patients with Fabry disease, with support from a multidisciplinary clinical team including nephrology, cardiology, medical genetics, neurology, psychology, and nursing [19].

5.1 Adult Fabry patients

As indicated in the clinical studies above, early initiation of ERT seemed associated with more clinical benefits. For adult patients, in our practice, we follow the expert guideline from an international panel of Fabry disease experts from multiple subspecialties published in 2018 [19] and outlined below:

  • For all adult male patients with GLA variants consistent with classic Fabry disease, ERT should be initiated regardless of Fabry symptoms [19].

  • For adult symptomatic female patients with GLA variants consistent with classic Fabry disease and clinical signs/symptoms suggesting major organ involvement, initiation of ERT should be considered. The signs/symptoms include proteinuria/albuminuria not attributable to other causes, evidence of renal impairment (may require renal biopsy if isolated); stroke or TIA; neuropathic pain, pain crises, Fabry disease neuropathy; symptomatic cardiac disease not due to other causes (dyspnea, palpitations, syncope, chest pain); exercise intolerance and impaired sweating; recurrent diarrhea, chronic, disabling GI dysfunction (excluding alternative causes) [19].

  • For adult, asymptomatic female patients with GLA variants consistent with classic Fabry disease with laboratory, histological, or imaging evidence of injury to the kidney, heart, or the CNS, ERT should be also considered. The evidence includes decreased GFR (< 90 mL/min/1.73 m [2] adjusted for age > 40 years), persistent albuminuria >30 mg/g, renal biopsy proved podocyte foot process effacement or glomerulosclerosis, moderate or severe Gb3 inclusions in a range of renal cell types; silent strokes, cerebral white matter lesions on brain MRI; asymptomatic cardiac disease including cardiomyopathy, arrhythmia, or cardiac fibrosis on contrast cardiac MRI. Predominant expression of the mutant GLA allele is generally associated with rapid disease progression, requiring closer monitoring and early therapeutic intervention. If a skewed X-chromosome inactivation pattern with predominant expression of the mutant GLA allele has been demonstrated in the presence of signs and symptoms of disease, experts suggested ERT should also be considered [19].

  • For adult male and female patients with GLA variants consistent with later-onset Fabry disease or missense GLA variants of unknown significance (VUS), experts suggest ERT should be considered and is appropriate if there is a laboratory, histological, or imaging evidence of injury to the kidney, heart, or the CNS attributable to Fabry disease, even in the absence of typical Fabry symptoms. The interpretation of the pathogenicity of any VUS should involve an expert in genetics and management of Fabry disease. Individuals with well-characterized benign GLA polymorphisms should not be treated with ERT [19]. For patients without Fabry disease-related tissue pathology or clinical symptoms, particularly heterozygous female patients, some experts suggested a “wait and watch” approach to monitor patients regularly by a multidisciplinary care team [19].

5.2 Pediatric Fabry patients

In the pediatric population, renal damage is typically subclinical and identifiable only through biopsy. In young patients with Fabry disease, timely initiation of ERT is important because some early pathological changes are potentially reversible by ERT [42, 43]. As discussed above, the 10-year study of the effectiveness of agalsidase beta in patients with classic Fabry disease has demonstrated that adults who initiated treatment at a younger age and with less renal involvement benefited more from therapy [17, 42]. Therefore, early diagnosis of patients with Fabry disease is vital for appropriate management and monitoring. In our practice, we follow the consensus guideline developed by specialists from the United States with expertise in Fabry disease about the management and treatment of children with Fabry disease [42], which has considerable overlap but also some differences compared to the recommendations by the European Fabry Working Group [44].

  • For symptomatic boys and girls, the experts in the United States recommended treatment with ERT should be considered and is appropriate if Fabry symptoms are present at any age [42]. Symptomatic girls and boys should be treated and managed in the same way, with the goal of decreasing symptomatology and reducing the risk of disease progression [42]. These recommendations are similar to those by the European Fabry Working Group [44]. Girls with Fabry disease commonly develop nonspecific early symptoms, such as abdominal pain, diarrhea, and neuropathic pain, around the age of 9–10 years [42, 45]. These symptoms should be considered adequate evidence of progressive disease to recommend the initiation of ERT [42].

  • For asymptomatic boys with GLA variants consistent with classic Fabry disease, experts in the United States recommend the timing of ERT depending on the individual case, carefully balancing the risks and benefits of therapy. Clinicians should have a serious discussion with the family to consider initiation of ERT by age 8–10 years [42]. This consensus recommendation was reached based on data from renal biopsy studies and responses to ERT that noted the greater difficulty in initiating infusions in children younger than this age [42]. These United States consensus recommendations do not concur with the European Fabry Working Group recommendations for treatment initiation at 16 years [42, 44].

  • For asymptomatic girls and asymptomatic boys with late-onset variants or VUS, the decision to defer ERT should be based on comprehensive longitudinal monitoring for the development of clinical symptoms and signs of disease. The family history of the female patients should also be considered [42].

5.3 Dosing and duration of therapy

As mentioned above, the two widely used forms of ERT for Fabry disease are agalsidase alfa and agalsidase beta and there have not been any trials comparing these formulations to one another [46].

The formulations of agalsidase alfa and agalsidase beta are structurally very similar to one another [47, 48, 49], however, they are not dosed the same. Agalsidase alfa is dosed at 0.2 mg/kg every other week [50],while agalsidase beta is dosed at 1.0 mg/kg every other week [51]. For patients who weigh less than 30 kg, the infusion rate of agalsidase beta should not exceed 15 mg/hr.

There are no clinical trials to determine the duration of ERT [52] in patients that meet the criteria to be treated, however, treatment is generally continued until a reason for stopping therapy arises. The most agreed-upon reasons for stopping therapy are noncompliance with infusions, failure to attend regular follow up visits, end-stage Fabry disease or other co-morbidities leading to a life expectancy of <1 year, lack of response for 1 year when the sole indication for ERT is neuropathic pain while receiving maximum supportive care, or persistent life-threatening or severe reactions that do not respond to prophylaxis and patient request [44].

The Fabry registry website includes a detailed table resource that can be used as a visual to guide a prescriber on what lab values, imaging, and other studies should be monitored, specifically in the pediatric population. This can be found in the Fabry Registry section entitled “Fabry Registry Recommended Schedule of Assessments.” The page can be found using the following web address:

5.4 Side effects and what to monitor in patients receiving ERT

The side effects of ERT that were mentioned in the early trials included side effects that are common with infusions including fevers and rigors. These infusion-associated reactions are often treated prophylactically with antihistamines, acetaminophen, and pre-infusion steroids sometimes becoming necessary. It is not uncommon that lengthening of infusion times becomes necessary because of these reactions [39, 50]. There have been reported life-threatening infusion-associated reactions, although those are rare [53].

Expert recommendations have been used to determine potential scheduled assessment and monitoring. The patient will undergo the most amount of testing upon initial evaluation including a full medical history (including family history, physical examination, vital signs, and quality of life), basic metabolic panel, urine protein excretion, lipid panels, and other measures for cardiac, cerebrovascular, neurological, ENT, pulmonary, and ophthalmological assessments. Plasma samples for Gb3 testing should be drawn prior to the first infusion, then every 3 months for the first 18 months of treatment, then every 6 months thereafter. It is reasonable to do a monitoring of serum chemistries and a complete blood count every 6–12 months in all patients. In patients with kidney disease, consider monitoring urinary protein excretion every 3 months. All patients regardless of renal involvement should have annual urinary protein measurement. A baseline kidney biopsy can serve as a potential marker to assess disease progression if the patient experiences deterioration of his/her condition and a repeat biopsy is warranted [19].

The formation of neutralizing antidrug antibodies (ADAs) is not uncommon in patients with Fabry disease receiving ERT [50, 54, 55]. These antibodies are associated with increased accumulation of plasma globotriaosylceramide and disease progression [56]. An open cohort study showed ADA titers decreased significantly in all patients with Fabry disease during ERT infusion and that a not saturated ADA status during infusion is associated with progressive loss of eGFR and ongoing cardiac hypertrophy. Dose escalation can result in saturation of ADAs and decreasing Gb3 levels but may lead to increased ADA titers [56]. Immunosuppression may be considered should ADAs develop but it is not clear how much long-term protection it can offer. Serum samples for IgG antibody testing should be drawn prior to the first infusion, then every 3 months for the first 18 months of treatment, then every 6 months until two consecutive negative results are confirmed.

5.5 Creating a protocol in the infusion center

Patients with Fabry disease need ERT infusions every other week. The information needed for drug administration often comes from the manufacturer. The information we supply here is for agalsidase beta and serves as an example of what kind of resources would be needed to create a protocol and provide this medication at an infusion center.

Agalsidase beta comes in 5 mg and 35 mg vials that are initially injected with sterile water to create a colorless solution. This solution is then further diluted with 0.9% sodium chloride that is diluted to a higher volume, which is supplied by the manufacturer. Once the diluted solution is created, it is recommended that it be used immediately. If that is not possible, the solution can be stored for 24 h at a temperature of 2–8°C. The initial infusion rate of the solution should be no more than 15 mg/h and this can be slowed down further for infusion-associated reactions. For patients that weigh >30 kg and after the infusion is well-tolerated, the infusion rate can be increased by 3–5 mg/h with each infusion. The minimal infusion time for patients >30 kg should be 1.5 h.

Antipyretics are recommended to be administered prior to the enzymatic infusion. If a patient experiences an infusion-associated reaction, options include decreasing the infusion rate, temporarily stopping the infusion, and/or administering additional antipyretics, antihistamines, and/or steroids if needed. Prophylactic antihistamines and/or steroids can be considered in patients who experience infusion-related reactions. Life-threatening anaphylactic reactions can occur and require immediate discontinuation of the infusion as well as a center that is equipped with appropriate medical support measures and the capability to handle such scenarios.

5.6 Cost

ERT is expensive. The estimated retail cost of therapy with Fabrazyme for 1 year is approximately USD 300,000 in the United States and Europe.


6. Summary

In short, Fabry disease is a multi-systemic disease associated with a high burden of morbidity and mortality.

The clinical outcome of patients with Fabry disease has drastically changed with the introduction of ERT. Timely initiation of ERT and regular assessments of disease progression by a multidisciplinary care team are critical for the long-term management of patients with Fabry disease.


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Written By

Hanny Sawaf, Angelika L. Erwin, Fang Zhao, Tushar J. Vachharajani and Xiangling Wang

Submitted: 20 November 2021 Reviewed: 18 February 2022 Published: 05 May 2022